Carl Nathan
Weill Cornell Medical College, New York
Genes required by Mycobacterium tuberculosis to survive transmission
Mycobacterium tuberculosis (Mtb), a leading cause of death from infection, completes its life cycle entirely in humans except for transmission through air. To understand how Mtb survives aerosolization, we mimicked liquid and atmospheric conditions experienced by Mtb before and after exhalation using a model aerosol fluid (MAF) based on the water-soluble, lipidic and cellular constituents of necrotic tuberculosis lesions. MAF induced drug tolerance in Mtb, remodeled its transcriptome and protected Mtb from dying in microdroplets desiccating in air. Yet survival was not passive: Mtb appeared to rely on hundreds of its genes to survive conditions associated with transmission. Among essential genes, those subserving proteostasis offered most protection. A large number of conventionally nonessential genes appeared to contribute as well, including genes encoding proteins that resemble anti-desiccants. The transmission survival genome of Mtb may offer opportunities to reduce transmission of tuberculosis.
References
- Nathan, C. Microbe Matters: Mycobacterium tuberculosis as teacher. Nature Microbiology 8: 1606-1608 2023
- Nathan, C. Nonresolving inflammation redux. Immunity 55: 592-605, 2022
- Singh, A.*, S. Ottavi*, I. Krieger, K. Planck, A. Perkowski, T. Kaneko, A. M. Davis, C. Suh, D. Zhang, L. Goullieux, A. Alex, C. Roubert, M. Gardner, M. Preston, D. M. Smith, Y. Ling, J. Roberts, B. Cautain, A. Upton, C. B. Cooper, N. Serbina, Z. Tanvir, J. Mosior, O. Ouerfelli, G. Yang, B. S. Gold, K. Y. Rhee, J. C. Sacchettini, N. Fotouhi†, J. Aubé† and C. Nathan†. *co-first authors. †co-senior authors. Redirecting raltitrexed from cancer cell thymidylate synthase to Mycobacterium tuberculosis phosphopantetheinyl transferase. Sciences Advances 10: eadj6406, 1-17, 2024
- Zhan, W., D. Li, S. B. S., Y. J. Liu, C. Yang, H. Zhang, J. C. Harris, R. Wang, S. Zhu, J. Sherman, J. Qin, N. V. Simwela, A. P. Waters, G. Sukenick, L. Cui, A. Rodriguez, H. Deng, C. F. Nathan, L. A. Kirkman, G. Lin. Identification of artezomibs, dual-pharmacophores that hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance. Cell Chemical Biology 30: 1-13, 2023
- Saito, K., S. Mishra, T. Warrier, N. Cicchetti, J. Mi, E. Weber, J. Roberts, A. Gouzy, E. Kaplan, C. D. Brown, B. Gold and C. Nathan. Oxidative damage and delayed replication allow viable Mycobacteriumtuberculosis to go undetected. Science Translational Medicine 13: eabg2612, 2021